The aim of this project is to study the prolonged effects of hemorrhage, endotoxin, transfusion, and overtransfusion on net transvascular fluid fluxes in skin, skeletal muscle, and intestine in both canine and primate (baboon) circulatory shock models to determine if net fluid filtration is a determinant of irreversible shock. Additionally, the effects of ischemia and various edemogenic substances released in shock states on fluid filtration will also be investigated. Particular attention will be paid to the role of microvascular pressure per se and pressure dependent and pressure independent increases in microvascular protein permeability in the genesis of edema formation. A more complete understanding of these interrelationships will provide a better understanding of the basic physiology of edema formation, the mechanism of action of these edemogenic substances, and the relative contribution of these factors to fluid filtration in circulatory shock states. Another aim of this project will be to investigate the role of central nervous system mediated cardiovascular actions in the genesis of endotoxin shock utilizing the cross-circulation technique of Buckley. Recent data suggest that endotoxin either directly or indirectly, at least under certain unique experimental conditions, affects CNS cardiovascular centers eliciting most of the hemodynamic alterations associated with endotoxin shock. To date there is no information on whether intravenous administration of endotoxin can affect these same brain sites. Utilizing the Buckley cross-circulation preparation in which there is absolutely no circulatory leakage between the head and trunk of the animal it will be possible to make a definitive statement regarding the central nervous system mediated cardiovascular effects of intravenously administered endotoxin.